Chlorogenic acid induces apoptosis to inhibit inflammatory proliferation of IL-6-induced fibroblast-like synoviocytes through modulating the activation of JAK/STAT and NF-κB signaling pathways

Lou,Lixia; Zhou,Jingwei; Liu,Yujun; Wei,Yi; Zhao,Jiuli; Deng,Jiagang; Dong,Bin; Zhu,Lingqun; Wu,Aiming; Yang,Yingxi; Chai,Limin

doi:10.3892/etm.2016.3136

Chlorogenic acid induces apoptosis to inhibit inflammatory proliferation of IL-6-induced fibroblast-like synoviocytes through modulating the activation of JAK/STAT and NF-κB signaling pathways

Authors:
- Lixia Lou
- Jingwei Zhou
- Yujun Liu
- Yi Wei
- Jiuli Zhao
- Jiagang Deng
- Bin Dong
- Lingqun Zhu
- Aiming Wu
- Yingxi Yang
- Limin Chai
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Affiliations: Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, P.R. China, Department of Renal Endocrinology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, P.R. China, Department of Rheumatology, Putuo District Center Hospital, Shanghai 200000, P.R. China, School of Pharmacy, Guangxi University of Chinese Medicine, Nanning, Guangxi 530001, P.R. China
Published online on: March 9, 2016 https://doi.org/10.3892/etm.2016.3136
Pages: 2054-2060

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Abstract

Chlorogenic acid (CGA) is the primary constituent of Caulis Lonicerae, a Chinese herb used for the treatment of rheumatoid arthritis (RA). The present study aimed to investigate whether CGA was able to inhibit the proliferation of the fibroblast-like synoviocyte cell line (RSC‑364), stimulated by interleukin (IL)-6, through inducing apoptosis. Following incubation with IL-6 or IL-6 and CGA, the cellular proliferation of RSC‑364 cells was detected by MTT assay. The ratio of apoptosed cells were detected by flow cytometry. Western blot analysis was performed to observe protein expression levels of key molecules involved in the Janus‑activated kinase/signal transducer and activator of transcription 3 (JAK/STAT) signaling pathway [phosphorylated (p)‑STAT3, JAK1 and gp130] and the nuclear factor κB (NF‑κB) signaling pathway [phosphorylated (p)‑inhibitor of κB kinase subunit α/β and NF‑κB p50). It was revealed that CGA was able to inhibit the inflammatory proliferation of RSC‑364 cells mediated by IL‑6 through inducing apoptosis. CGA was also able to suppress the expression levels of key molecules in the JAK/STAT and NF‑κB signaling pathways, and inhibit the activation of these signaling pathways in the inflammatory response through IL‑6‑mediated signaling, thereby resulting in the inhibition of the inflammatory proliferation of synoviocytes. The present results indicated that CGA may have potential as a novel therapeutic agent for inhibiting inflammatory hyperplasia of the synovium through inducing synoviocyte apoptosis in patients with RA.

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1	Gibofsky A: Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis. Am J Manag Care. 18:S295–S302. 2012.PubMed/NCBI
2	Semerano L, Minichiello E, Bessis N and Boissier MC: Novel immunotherapeutic avenues for rheumatoid arthritis. Trends Mol Med. 22:214–229. 2016. View Article : Google Scholar : PubMed/NCBI
3	Müller-Ladner U, Pap T, Gay RE, Neidhart M and Gay S: Mechanisms of disease: The molecular and cellular basis of joint destruction in rheumatoid arthritis. Nat Clin Pract Rheumatol. 1:102–110. 2005. View Article : Google Scholar : PubMed/NCBI
4	Firestein GS: Evolving concepts of rheumatoid arthritis. Nature. 423:356–361. 2003. View Article : Google Scholar : PubMed/NCBI
5	Bartok B and Firestein GS: Fibroblast-like synoviocytes: Key effector cells in rheumatoid arthritis. Immunol Rev. 233:233–255. 2010. View Article : Google Scholar : PubMed/NCBI
6	Huber LC, Distler O, Tarner I, Gay RE, Gay S and Pap T: Synovial fibroblasts: Key players in rheumatoid arthritis. Rheumatology (Oxford). 45:669–675. 2006. View Article : Google Scholar : PubMed/NCBI
7	Hirano T: Interleukin 6 and its receptor: Ten years later. Int Rev Immunol. 16:249–284. 1998. View Article : Google Scholar : PubMed/NCBI
8	Okamoto H, Yamamura M, Morita Y, Harada S, Makino H and Ota Z: The synovial expression and serum levels of interleukin-6, interleukin-11, leukemia inhibitory factor, and oncostatin M in rheumatoid arthritis. Arthritis and Rheum. 40:1096–1105. 1997. View Article : Google Scholar
9	Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G, Tang B, Sato K, Shimizu M, Maini R, Feldmann M, et al: Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol. 18:1797–1801. 1988. View Article : Google Scholar : PubMed/NCBI
10	Dasgupta B, Corkill M, Kirkham B, Gibson T and Panayi G: Serial estimation of interleukin 6 as a measure of systemic disease in rheumatoid arthritis. J Rheumatol. 19:22–25. 1992.PubMed/NCBI
11	Ishihara K and Hirano T: IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev. 13:357–368. 2002. View Article : Google Scholar : PubMed/NCBI
12	Feldmann M, Brennan FM and Maini RN: Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 14:397–440. 1996. View Article : Google Scholar : PubMed/NCBI
13	Alonzi T, Fattori E, Lazzaro D, Costa P, Probert L, Kollias G, De Benedetti F, Poli V and Ciliberto G: Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med. 187:461–468. 1998. View Article : Google Scholar : PubMed/NCBI
14	Ohshima S, Saeki Y, Mima T, Sasai M, Nishioka K, Nomura S, Kopf M, Katada Y, Tanaka T, Suemura M and Kishimoto T: Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc Natl Acad Sci USA. 95:8222–8226. 1998. View Article : Google Scholar : PubMed/NCBI
15	Hirano T, Ishihara K and Hibi M: Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene. 19:2548–2556. 2000. View Article : Google Scholar : PubMed/NCBI
16	Kong X, Liu C, Zhang C, Zhao J, Wang J, Wan H, Zhu H, Zhang P, Chen W, Xiao Y and Lin N: The suppressive effects of Saposhnikovia divaricata (Fangfeng) chromone extract on rheumatoid arthritis via inhibition of nuclear factor-κB and mitogen activated proteinkinases activation on collagen-induced arthritis model. J Ethnopharmacol. 148:842–850. 2013. View Article : Google Scholar : PubMed/NCBI
17	Andreas K, Lübke C, Häupl T, Dehne T, Morawietz L, Ringe J, Kaps C and Sittinger M: Key regulatory molecules of cartilage destruction in rheumatoid arthritis: An in vitro study. Arthritis Res Ther. 10:R92008. View Article : Google Scholar : PubMed/NCBI
18	Ruan Z, Liu S, Zhou Y, Mi S, Liu G, Wu X, Yao K, Assaad H, Deng Z, Hou Y, et al: Chlorogenic acid decreases intestinal permeability and increases expression of intestinal tight junction proteins in weaned rats challenged with LPS. PLoS One. 9:e978152014. View Article : Google Scholar : PubMed/NCBI
19	dos Santos MD, Almeida MC, Lopes NP and de Souza GE: Evaluation of the anti-inflammatory, analgesic and antipyretic activities of the natural polyphenol chlorogenic acid. Biol Pharm Bull. 29:2236–2240. 2006. View Article : Google Scholar : PubMed/NCBI
20	Tatefuji T, Izumi N, Ohta T, Arai S, Ikeda M and Kurimoto M: Isolation and identification of compounds from Brazilian propolis which enhance macrophage spreading and mobility. Biol Pharm Bull. 19:966–970. 1996. View Article : Google Scholar : PubMed/NCBI
21	Wang J, Ma J, Dong L, Hou Y, Jia X, Niu X and Fan Y: Effect of anatase TiO2 nanoparticles on the growth of RSC-364 rat synovial cell. J Nanosci Nanotechnol. 13:3874–3879. 2013. View Article : Google Scholar : PubMed/NCBI
22	Guo HF, Liu SX, Zhang YJ, Liu QJ, Hao J and Gao LX: High mobility group box 1 induces synoviocyte proliferation in rheumatoid arthritis by activating the signal transducer and activator transcription signal pathway. Clin Exp Med. 11:65–74. 2011. View Article : Google Scholar : PubMed/NCBI
23	Kwak SC, Lee C, Kim JY, Oh HM, So HS, Lee MS, Rho MC and Oh J: Chlorogenic acid inhibits osteoclast differentiation and bone resorption by down-regulation of receptor activator of nuclear factor kappa-B ligand-induced nuclear factor of activated T cells c1 expression. Biol Pharm Bull. 36:1779–1786. 2013. View Article : Google Scholar : PubMed/NCBI
24	Fan L, Wang Q, Liu R, Zong M, He D, Zhang H, Ding Y and Ma J: Citrullinated fibronectin inhibits apoptosis and promotes the secretion of pro-inflammatory cytokines in fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res Ther. 14:R2662012. View Article : Google Scholar : PubMed/NCBI
25	Li G, Liu D, Guo S, Sunagawa M, Hisamitsu T and Liu Y: Anti-invasive effects of Celastrus Orbiculatus extract on interleukin-1 beta and tumour necrosis factor-alpha combination-stimulated fibroblast-like synoviocytes. BMC Complement Altern Med. 14:622014. View Article : Google Scholar : PubMed/NCBI
26	Marinova-Mutafchieva L, Williams RO, Funa K, Maini RN and Zvaifler NJ: Inflammation is preceded by tumor necrosis factor-dependent infiltration of mesenchymal cells in experimental arthritis. Arthritis and Rheum. 46:507–513. 2002. View Article : Google Scholar
27	Nakajima T, Aono H, Hasunuma T, Yamamoto K, Shirai T, Hirohata K and Nishioka K: Apoptosis and functional Fas antigen in rheumatoid arthritis synoviocytes. Arthritis and Rheum. 38:485–491. 1995. View Article : Google Scholar
28	Liu YJ, Zhou CY, Qiu CH, Lu XM and Wang YT: Chlorogenic acid induced apoptosis and inhibition of proliferation in human acute promyelocytic leukemia HL60 cells. Mol Med Rep. 8:1106–1110. 2013.PubMed/NCBI
29	Wu C, Luan H, Zhang X, Wang S, Zhang X, Sun X and Guo P: Chlorogenic acid protects against atherosclerosis in ApoE-/- mice and promotes cholesterol efflux from RAW264.7 macrophages. PLoS One. 9:e954522014. View Article : Google Scholar : PubMed/NCBI
30	Guo YJ, Luo T, Wu F, Mei YW, Peng J, Liu H, Li HR, Zhang SL, Dong JH, Fang Y and Zhao L: Involvement of TLR2 and TLR9 in the anti-inflammatory effects of chlorogenic acid in HSV-1-infected microglia. Life Sci. 127:12–18. 2015. View Article : Google Scholar : PubMed/NCBI
31	Migita K, Komori A, Torigoshi T, Maeda Y, Izumi Y, Jiuchi Y, Miyashita T, Nakamura M, Motokawa S and Ishibashi H: CP690,550 inhibits oncostatin M-induced JAK/STAT signaling pathway in rheumatoid synoviocytes. Arthritis Res Ther. 13:R722011. View Article : Google Scholar : PubMed/NCBI
32	Borie DC, O'Shea JJ and Changelian PS: JAK3 inhibition, a viable new modality of immunosuppression for solid organ transplants. Trends Mol Med. 10:532–541. 2004. View Article : Google Scholar : PubMed/NCBI
33	Hayden MS and Ghosh S: Shared principles in NF-kappaB signaling. Cell. 132:344–362. 2008. View Article : Google Scholar : PubMed/NCBI